Challenges in the Development of Rodent Models of Mild Traumatic Brain Injury

Authors: Dewitt D, Perez-Polo JR Ph D, Hulsebosch C, Dash PK, Robertson CS.

Approximately 75% of traumatic brain injuries (TBI) are classified mild (mTBI). Despite the high frequency of mTBI, it is the least well studied. The prevalence of mTBI among service personnel returning from Operations Iraqi Freedom (OIF) and Enduring Freedom (OEF) and the recent reports of an association between repeated mTBI and the early onset of Alzheimer's and other types of dementias in retired athletes has focused much attention on mTBI. The study of mTBI requires the development and validation of experimental models of mTBI and one of the most basic requirements for an experimental model is that it replicates important features of the injury or disease in humans. mTBI in humans is associated with acute symptoms such as loss of consciousness and pre- and/or posttraumatic amnesia. In addition, although the majority of patients recover within a few months after mTBI, a small but significant number (2.5 - 26%) had Glasgow Outcome Scores in the "moderate disability" range. These mTBI patients experienced long-term effects of mTBI including deficits in speed of information processing, attention and concentration, memory acquisition, retention and retrieval and reasoning and decision-making. Although methods for the diagnosis and evaluation of the acute and chronic effects of mTBI in humans are well established, the same is not the case for rodents, the most widely used animal for TBI studies. Despite the magnitude of the difficulties associated with adapting these methods for experimental mTBI research, they must be surmounted. The identification and testing of treatments for mTBI depends of the development, characterization and validation of reproducible, clinically relevant models of mTBI.

Tissue vulnerability is increased following repetitive mild traumatic brain injury in the rat

Authors: Huang L, Coats JS, Mohd-Yusof A, Yin Y, Assaad S, Muellner MJ, Kamper JE, Hartman RE, Dulcich M, Donovan VM, Oyoyo U, Obenaus A.

Repetitive mild traumatic brain injury (rmTBI) is an important medical concern for active sports and military personnel. Multiple mild injuries may exacerbate tissue damage resulting in cumulative brain injury and poor functional recovery. In the present study, we investigated the time course of brain vulnerability to rmTBI in a rat model of mild cortical controlled impact. An initial mild injury was followed by a second injury unilaterally at an interval of 1, 3, or 7 days. RmTBI animals were compared to single mTBI and sham treated animals. Neuropathology was assessed using multi-modal magnetic resonance imaging (MRI), followed by ex vivo tissue immunohistochemistry. Neurological and behavioral outcomes were evaluated in a subset of animals receiving rmTBI 3 days apart and shams. RmTBI 1 or 3 days apart but not 7 days apart revealed significantly exacerbated MRI-definable lesion volumes compared to single mTBI and shams. Increases in cortical tissue damage, extravascular iron and glial activation assessed by histology/immunohistochemistry correlated with in vivo MRI findings where shorter intervals (1 or 3 days apart) resulted in increased tissue pathology. There were no neurological deficits associated with rmTBI 3 day animals. At 1 mo post-injury, animals with rmTBI 3 days apart showed reduced exploratory behaviors and subtle spatial learning memory impairments were observed. Collectively, our findings suggest that the mildly-impacted brain is more vulnerable to repetitive injury when delivered within 3 days following initial mTBI.

Neuropathology of Explosive Blast Traumatic Brain Injury

Authors: Magnuson J, Leonessa F, Ling GS.

During the conflicts of the Global War on Terror, which are Operation Enduring Freedom (OEF) in Afghanistan and Operation Iraqi Freedom (OIF), there have been over a quarter of a million diagnosed cases of traumatic brain injury (TBI). The vast majority are due to explosive blast. Although explosive blast TBI (bTBI) shares many clinical features with closed head TBI (cTBI) and penetrating TBI (pTBI), it has unique features, such as early cerebral edema and prolonged cerebral vasospasm. Evolving work suggests that diffuse axonal injury (DAI) seen following explosive blast exposure is different than DAI from focal impact injury. These unique features support the notion that bTBI is a separate and distinct form of TBI. This review summarizes the current state of knowledge pertaining to bTBI. Areas of discussion are: the physics of explosive blast generation, blast wave interaction with the bony calvarium and brain tissue, gross tissue pathophysiology, regional brain injury, and cellular and molecular mechanisms of explosive blast neurotrauma.

Traumatic Brain Injury, Shell Shock, and Posttraumatic Stress Disorder in the Military—Past, Present, and Future

Authors: Shively, Sharon B. MD, PhD; Perl, Daniel P. MD

With preferential use of high explosives in modern warfare, traumatic brain injury (TBI) has become a common injury for troops. Most TBIs are classified as “mild,” although military personnel with these injuries can have persistent symptoms such as headache, memory impairment, and behavioral changes. During World War I, soldiers in the trenches, undergoing unrelenting artillery bombardment, suffered from similar symptoms, designated at the time as “shell shock.” Dr Frederick Mott proposed studying the brains of deceased soldiers to elucidate the neuropathology of this clinical entity. Subsequent to a British government enquiry after World War I, the term “shell shock” was banned and further investigation into a possible organic cause for these symptoms was discontinued. Nevertheless, similar clinical entities, such as combat or battle fatigue and posttraumatic stress disorder, continue to be encountered by combatants in subsequent military conflicts. To this day, there exists a paucity of neuropathology studies investigating the effects of high explosives on the human brain. By analogy, studies have recently revealed that athletes with repeated head trauma can develop a neurodegenerative disease, chronic traumatic encephalopathy, who present with similar clinical features. Given current circumstance, we propose completing the work envisioned by Dr Mott almost 100 years ago.

Effects of chronic mild traumatic brain injury on white matter integrity in Iraq and Afghanistan war veterans

Authors: Morey RA, Haswell CC, Selgrade ES, Massoglia D, Liu C, Weiner J, Marx CE, Cernak I, McCarthy G; MIRECC Work Group.

Mild traumatic brain injury (TBI) is a common source of morbidity from the wars in Iraq and Afghanistan. With no overt lesions on structural MRI, diagnosis of chronic mild TBI in military veterans relies on obtaining an accurate history and assessment of behavioral symptoms that are also associated with frequent comorbid disorders, particularly posttraumatic stress disorder (PTSD) and depression. Military veterans from Iraq and Afghanistan with mild TBI (n = 30) with comorbid PTSD and depression and non-TBI participants from primary (n = 42) and confirmatory (n = 28) control groups were assessed with high angular resolution diffusion imaging (HARDI). White matter-specific registration followed by whole-brain voxelwise analysis of crossing fibers provided separate partial volume fractions reflecting the integrity of primary fibers and secondary (crossing) fibers. Loss of white matter integrity in primary fibers (P < 0.05; corrected) was associated with chronic mild TBI in a widely distributed pattern of major fiber bundles and smaller peripheral tracts including the corpus callosum (genu, body, and splenium), forceps minor, forceps major, superior and posterior corona radiata, internal capsule, superior longitudinal fasciculus, and others. Distributed loss of white matter integrity correlated with duration of loss of consciousness and most notably with "feeling dazed or confused," but not diagnosis of PTSD or depressive symptoms. This widespread spatial extent of white matter damage has typically been reported in moderate to severe TBI. The diffuse loss of white matter integrity appears consistent with systemic mechanisms of damage shared by blast- and impact-related mild TBI that involves a cascade of inflammatory and neurochemical events. Hum Brain Mapp , 2012. © 2012 Wiley Periodicals, Inc.

A Multiscale Approach to Blast Neurotrauma Modeling: Part I - Development of Novel Test Devices for in vivo and in vitro Blast Injury Models

Authors: Panzer MB, Matthews KA, Yu AW, Morrison B 3rd, Meaney DF, Bass CR.

The loading conditions used in some current in vivo and in vitro blast-induced neurotrauma models may not be representative of real-world blast conditions. To address these limitations, we developed a compressed-gas driven shock tube with different driven lengths that can generate Friedlander-type blasts. The shock tube can generate overpressures up to 650 kPa with durations between 0.3 and 1.1 ms using compressed helium driver gas, and peak overpressures up to 450 kPa with durations between 0.6 and 3 ms using compressed nitrogen. This device is used for short-duration blast overpressure loading for small animal in vivo injury models, and contrasts the more frequently used long duration/high impulse blast overpressures in the literature. We also developed a new apparatus that is used with the shock tube to recreate the in vivo intracranial overpressure response for loading in vitro culture preparations. The receiver device surrounds the culture with materials of similar impedance to facilitate the propagation of a single overpressure pulse through the tissue. This method prevents pressure waves reflecting off the tissue that can cause unrealistic deformation and injury. The receiver performance was characterized using the longest helium-driven shock tube, and produced in-fluid overpressures up to 1500 kPa at the location where a culture would be placed. This response was well correlated with the overpressure conditions from the shock tube (R(2) = 0.97). Finite element models of the shock tube and receiver were developed and validated to better elucidate the mechanics of this methodology. A demonstration exposing a culture to the loading conditions created by this system suggest tissue strains less than 5% for all pressure levels simulated, which was well below functional deficit thresholds for strain rates less than 50 s(-1). This novel system is not limited to a specific type of culture model and can be modified to reproduce more complex pressure pulses.


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